Project Summary/Abstract Two primary roles of the stomach are to digest food and destroy ingested pathogens. However, the harsh, acidic stomach environment, while necessary for function, must be balanced with secretion of protective mucous and tissue regeneration to prevent tissue damage and disease. In addition, immune system is an important regulator of stomach health. Immune function must balance between necessary removal of cellular debris and protection from infection but avoid autoimmune reaction and chronic inflammation. Dysregulation of stomach and/or the immune system can result in gastric cancer, which is the third leading cause of cancer deaths worldwide. Glucocorticoids are primary stress hormones that function to suppress inflammation, direct wound healing, and direct cellular differentiation in a variety of tissues and organ systems. Disrupted glucocorticoids signaling is associated with a plethora of diseases including autoimmune disease, chronic inflammatory disease, heart disease, and a wide variety of cancers. Surprisingly, the role of glucocorticoids in the stomach remains unknown. We recently discovered that glucocorticoid signaling is required for stomach health and function in mice. Systemic removal of glucocorticoids by adrenalectomy caused gastric gland atrophy, mucous cell metaplasia, and chronic inflammation. Closer analysis revealed nearly complete loss of parietal and chief cells and hyperplasia of mucous neck cells. The gastric pathology was completely reversed after 2 weeks of glucocorticoid replacement therapy. In the proposed aims, we will determine the impact of long-term glucocorticoid deficiency on stomach health and characterize the physiological mechanism(s) of glucocorticoid action in the stomach. In Aim 1, we will characterize the relative risk of stomach cancer following systemic removal of glucocorticoids. We predict that the observed gastric pathology will cause spontaneous development of gastric cancer. In Aim 2, we will determine the extent that autoimmunity or chronic inflammation contribute to the gastric pathology after adrenalectomy. In Aim 3, we will characterize how glucocorticoid signaling in parietal, chief, and mucous neck cells regulates their function, self-renewal, and maintains stomach health. At the conclusion of this study, we will have established the role of glucocorticoid signaling on stomach health and cancer prevention. These discoveries will open new avenues for future studies to elucidate the molecular mechanisms underlying glucocorticoid action in the stomach and define how glucocorticoids, by promoting tissue homeostasis, suppress formation of gastric cancer. !